Direct palladium-catalyzed arylation of cyclopropenes

Article abstract of DOI:10.1021/ja042380k

The first examples of direct palladium-catalyzed arylation and heteroarylation of cyclopropenes have been demonstrated. This method allows for efficient synthesis of various tetrasubstituted cyclopropenes, incuding nonracemic cyclopropenes, which are not available via known asymmetric cyclopropenation methods. Mechanistic studies strongly suggest an electrophilic path for this Heck-type transformation. Copyright

Full text of DOI:10.1021/ja042380k

Published on Web 03/01/2005
Direct Palladium-Catalyzed Arylation of Cyclopropenes
Stepan Chuprakov, Michael Rubin, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street Chicago, Illinois 60607-7061
Received December 18, 2004; E-mail: vlad@uic.edu
Table 1. Pd-Catalyzed Arylation of Cyclopropenes
As a result of their enormous ring strain, cyclopropenes display
an array of diverse reactivities in both noncatalytic1 and transition-
metal-catalyzed transformations,2 attracting increasing attention
from the synthetic community. Accordingly, a number of methods
for construction and further modification of cyclopropenes have
been developed. Noncatalytic methods involve trapping of nucleo-
philic cyclopropenyl metal species with various electrophiles.3
Introduction of aryl and vinyl substituents can be achieved via Pd-
catalyzed Negishi or Stille cross-coupling, reported by de Meijere4
and Fox3 (eq 1), or via Heck-type reaction of cyclopropenyl iodides
with acrylates, developed by Chen (eq 2).5 However, to date there
are no examples of Heck-type processes involving the double bond
of cyclopropene. Moreover, a single report exists on the attempted
transformation of this type, which resulted in the ring opening of
cyclopropene.6 Herein, we report the direct and efficient Heck-
type arylation of cyclopropenes proceeding with preservation of
the ring (eq 3).
Initially, we tested arylation of phenyl-substituted cyclopropene
1b under various Heck reaction conditions.7 We have found that
the catalyst system Pd(OAc)2 (5 mol %)/K2CO3 (2.5 equiv) in DMF
efficiently catalyzed arylation of 1a to give tetrasubstituted cyclo-
propene 3aa in 62% isolated yield (eq 4, Table 1, entry 1). Next,
the arylation of differently substituted cyclopropenes was examined
under these reaction conditions. Cyclopropenedicarboxylates 1a and
1b reacted smoothly with aryl iodides 2b,c, affording highly
functionalized tetrasubstituted cyclopropenes in high yields (entries
2-5). 3-Phenyl-containing cyclopropene 1c also provided good
yields in arylation with iodobenzenes 2b,c,f (entries 6, 7, and 10),
1-iodonaphthalene (entry 9), and heteroarylation with 2-iodo-
thiophene (entry 8). Likewise, nitroaryl-substituted cyclopropene
1d underwent smooth arylation under the above reaction conditions
(entry 11). n-Butyl-substituted cyclopropene 1e, in contrast to its
aryl analog 1a, reacted much more slowly and provided only a
moderate yield in this reaction (entry 12). Notably, 3,3-disubstituted
cyclopropene 1f (R1 ) CO2Me, R2 ) H) did not undergo the
arylation reaction at all.
a Isolated yields.
according to Davies’ protocol10b was subjected to the arylation under
standard conditions. As expected, the reaction proceeded unevent-
fully to provide (S)-3cb and (S)-3cc in excellent yields with
complete preservation of stereochemistry (eq 5).
We recognize that this methodology could be especially attractive
in application to nonracemic substrates, because it will allow for
direct8 synthesis of optically active tetrasubstituted cyclopropenes,
not available via asymmetric cyclopropenation methods.9,10 Ac-
cordingly, optically active cyclopropene (S)-1c, easily available
The mechanism of this reaction can be rationalized via several
alternative pathways including Heck-type, C-H activation, or cross-
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10.1021/ja042380k CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Alternative Mechanistic Rationales for Pd-Catalyzed
Arylation of Cyclopropenes
Acknowledgment. The support of the National Science Foun-
dation (CHE 0354613) is gratefully acknowledged.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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coupling protocols (Scheme 1). In the event that this arylation
proceeds via migratory insertion to form 4, followed by anti-â-
hydride elimination11 (path A), a substantial value of kinetic isotope
effect (KIE) should be expected.12 However, no KIE was observed
in this reaction (kH/kD ) 1.0), thus strongly opposing carbopalla-
dation path A.13 Alternatively, arylation of cyclopropenes may
proceed through a cationic path B (Scheme 1),14 involving
electrophilic addition of ArPd+ species to cyclopropene to form
cyclopropyl cation 5, followed by fast loss of the proton, which is
in agreement with the absence of KIE. Benzylic cation 5 (R2 )
Ar) is additionally stabilized by interaction with d-orbitals of Pd.15
If arylation proceeds through path B, then the reaction rates should
depend on the electronic nature of R2. Experiments met these
expectations: p-tolyl-substituted cyclopropene 1b reacted more
quickly than parent 1a, whereas introduction of a p-CO2Me group
(1g) suppressed the reaction (eq 6). In addition, less efficient
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(7) See Supporting Information for details.
(8) For preparation of tetrasubstituted nonracemic cyclopropenes via Negishi
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of enantioselectivity in reactions with terminal alkynes only; see: (a)
Doyle, M. P.; Protopopova, M.; Muller, P.; Ene, D.; Shapiro, E. A. J.
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(12) It is well-known that syn-â-hydride elimination experiences a substantial
kinetic isotope effect (KIE, typical values of kH/kD ) 2-3). See, for
example: (a) Takacs, J. M.; Lawson, E. C.; Clement, F. J. Am. Chem.
Soc. 1997, 119, 5956. (b) Netherton, M. R.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 3910. (c) Shmidt, A. F.; Smirnov, V. V. Kinet. Catal. 2001,
42, 800. The value of KIE for anti-â-hydride elimination is even higher
(kH/kD ) 5-7). See: Chrisope, D. R.; Beak, P.; Saunders, W. H., Jr. J.
Am. Chem. Soc. 1988, 110, 230. See also ref 12a.
stabilization of nonbenzylic cations 5, derived from 1e (R2 ) Alk)
and 1f (R2 ) H), is in good agreement with the observed decrease
in their reactivity (vide supra).
(13) Numerous attempts to perform reductive or cascade Heck reactions on
several cyclopropene-containing substrates have proved unsuccessful, as
well.
Two other possible mechanisms, involving C-H activation (path
C) and Sonogashira-like cross-coupling (path D, Scheme 1), were
essentially ruled out, as the former should experience a substantial
H/D KIE,16 whereas the latter is in conflict with our observations
of the lack of H/D scrambling in the starting material through the
course of the reaction.17 Furthermore, addition of Cu(I) or Ag(I)
salts, which are known to facilitate Sonogashira reaction,18 totally
inhibited the described process.
(14) For discussion on a cationic mechanism for Heck reaction, see: Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(15) For stabilization of cyclopropyl â-cation with d-elements, see: (a) de
Meijere, A.; Faber, D.; Heinecke, U.; Walsh, R.; Muller, T.; Apeloig, Y.
Eur. J. Org. Chem. 2001, 4, 663. (b) Surya Prakash, G. K.; Buchholz,
H.; Reddy, V. P.; de Meijere, A.; Olah, G. A. J. Am. Chem. Soc. 1992,
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2002, 124, 1586.
In summary, we have shown the first examples of direct Pd-
catalyzed arylation and heteroarylation of cyclopropenes. Mecha-
nistic data acquired to date strongly support electrophilic character
of this transformation. Further studies to set the scope and the
precise mechanism of this reaction are currently underway in our
laboratories.
(17) This approach was used to rule out Pd insertion in the C-H bond of
alkynes. See, for example: Kadnikov, D. V.; Larock, R. C. J. Organomet.
Chem. 2003, 687, 425.
(18) For a review, see for example: Sonogashira, K. Sonogashira Alkyne
Synthesis. In Handbook of Organopalladium Chemistry; Negishi, E., de
Meijere, A., Eds.; Wiley: New York, 2002; III.2.8.1., p 493.
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